SARS-CoV-2 infection is associated with anti-desmoglein 2 autoantibody detection

Abstract

Post-acute cardiac sequelae, following SARS-CoV-2 infection, are well recognized as complications of COVID-19. We have previously shown the persistence of autoantibodies against antigens in skin, muscle, and heart in individuals following severe COVID-19; the most common staining on skin tissue displayed an inter-cellular cement pattern consistent with antibodies against desmosomal proteins. Desmosomes play a critical role in maintaining the structural integrity of tissues. For this reason, we analyzed desmosomal protein levels and the presence of anti-desmoglein (DSG) 1, 2, and 3 antibodies in acute and convalescent sera from patients with COVID-19 of differing clinical severity. We find increased levels of DSG2 protein in sera from acute COVID-19 patients. Furthermore, we find that DSG2 autoantibody levels are increased significantly in convalescent sera following severe COVID-19 but not in hospitalized patients recovering from influenza infection or healthy controls. Levels of autoantibody in sera from patients with severe COVID-19 were comparable to levels in patients with non-COVID-19-associated cardiac disease, potentially identifying DSG2 autoantibodies as a novel biomarker for cardiac damage. To determine if there was any association between severe COVID-19 and DSG2, we stained post-mortem cardiac tissue from patients who died from COVID-19 infection. This confirmed DSG2 protein within the intercalated discs and disruption of the intercalated disc between cardiomyocytes in patients who died from COVID-19. Our results reveal the potential for DSG2 protein and autoimmunity to DSG2 to contribute to unexpected pathologies associated with COVID-19 infection.

Keywords: autoantibodies; autoimmunity; infection; virus.

Graphical Abstract

Figure 1.

Desmosome proteins detected in serum following SARS-CoV-2 infection. Detection of (A) desmoplakin (DSP, ***P = 0.0004), (B) junction plakoglobin (JUP), and (C) desmoglein 2 (DSG2, **P = 0.0051) protein by ELISA. Results are expressed as median concentration with interquartile range, and all groups are statistically not significant from healthy controls unless annotated.

Figure 2.

Desmoglein 2 IgG autoantibody concentrations are higher in patients post-severe SARS-CoV-2 infection. Detection of desmoglein 2 autoantibodies in COVID-19 cohorts by ELISA; convalescent COVID Intensive therapy unit (ITU), acute COVID ITU, and mild COVID convalescent, compared with non-COVID control cohorts; non-COVID ITU, Influenza (flu) ITU, and healthy controls (N = 252, P < 0.0001). The flu ITU, non-COVID ITU, and mild COVID convalescent cohorts were all not statistically significant compared to healthy controls. Results are expressed as median OD (optical density) with interquartile range. Figure in brackets indicates number of sera per group. **** indicates a significant difference between groups at a P value of <0.0001.

Figure 3.

Immunohistochemical staining of post-mortem cardiac tissue. (A) Non-COVID-19 post-mortem heart tissue shows uniform single-banded staining for DSG2 corresponding to the site of intercalated discs (these are indicated by black arrows). (B) Cardiac muscle from COVID-19 post-mortem cases showed areas of single and notable double banded staining for DSG2 (arrowed). (C) Post-mortem heart tissue from a non-COVID-19 patient stained for IgG deposition. (D) Post-mortem heart tissue from a COVID-19 patient demonstrating IgG deposition at intercalated discs. Images representative of 3 hearts from non-COVID-19 patients and 8 patients who died from COVID-19.